1. Field of the Invention
The present invention is directed to a method for preparing fluorinated organic compounds. More particularly, the present invention is directed to a method for the fluorodecarboxylation of halogenated aliphatic carboxylic acid compounds to form fluorinated organic products which are useful as inhalation anesthetics.
2. Description of the Prior Art
Anesthetics belong to a class of biochemical depressant drugs which affect the vital functions of all types of cells, especially nervous tissue cells. General anesthetics produce analgesia, loss of consciousness, diminished reflex activity, and muscular relaxation, with minimal depression of the vital functions. Anesthetics may be gaseous (volatile) or fixed (nonvolatile). Gaseous anesthetics are inhaled and enter the bloodstream through the lungs and fixed anesthetics are administered parenterally or through the alimentary canal.
Many currently used gaseous anesthetics are halogenated compounds. These compounds tend to cause less metabolic disturbance and are less flammable than traditional gaseous anesthetic compounds such as ether and cyclopropane. Examples of halogenated anesthetic compounds include halothane (CF.sub.3 CHBrCl) and trichloroethylene (Cl.sub.2 C.dbd.CHCl) as well as halogenated ether compounds such as enflurane (CHF.sub.2 OCF.sub.2 CHClF), fluroxene (CF.sub.3 CH.sub.2 OCH.dbd.CH.sub.2), methoxyflurane (Cl.sub.2 CHCF.sub.2 OCH.sub.3), and isoflurane (CF.sub.3 CHClOCHF.sub.2).
A particularly useful halogenated ether anesthetic is sevoflurane, (CF.sub.3).sub.2 CHOCH.sub.2 F, also known as 2-(fluoromethoxy)-1,1,1,3,3,3,-hexafluoropropane or fluoro-methyl-1,1,1,3,3,3-hexafluoro-2-propyl ether. Sevoflurane has a very low blood-gas solubility partition coefficient (0.6) which provides rapid equilibrium time, fast induction time and rapid recovery time. These properties make it especially useful for outpatient surgery, see D. F. Halpern, Chemtech. pp. 304-308 (May 1989).
The preparation of fluorinated compounds such as sevoflurane tends to be difficult because of the limited number of selective fluorination reactions available. Direct fluorination of organic compounds to replace hydrogen is statistical, non-selective and generally accompanied by the formation of many side products. Hence fluorinated compounds are usually prepared by first synthesizing a substituted organic intermediate, wherein the substituent group is at the site to be fluorinated, and then displacing the substituent group with a fluoride ion. Metal fluorides, for example, have been used to displace chlorine substituent groups.
U.S. Pat. No. 3,683,092, issued to Regan et al., discloses a method for synthesizing sevoflurane which comprises methylation of hexafluoroisopropyl alcohol followed by fluorination with either (a) bromine trifluoride or (b) chlorine gas followed by potassium fluoride.
U.S. Pat. No. 4,469,898, issued to Coon et al., discloses a method for synthesizing sevoflurane which comprises mixing hexafluoroisopropyl alcohol, formaldehyde, hydrogen fluoride, and a protonating, dehydrating and fluoride ion generating agent.
U.S. Pat. No. 4,874,901, issued to Halpern et al., discloses a method for fluorinating halogenated ether compounds. In particular, compounds such as sevoflurane can be prepared by reacting chloromethyl hexafluoroisopropyl ether with either potassium fluoride or sodium fluoride.
Patrick et al., J. Org. Chem., 48, 4158-4159 (1983), reports that alkyl carboxylic acids can be fluorodecarboxylated with xenon difluoride (XeF.sub.2) in the presence of hydrogen fluoride. Although the use of xenon difluoride on a small scale can be effective, the cost of xenon difluoride makes its use on large scale impractical. Furthermore, when alkoxyacetic acids are fluorodecarboxylated with xenon difluoride, significant amounts of side products are formed.
U.S. Pat. No. 4,847,427, issued to Nappa, discloses a method for preparing fluorocarbon polyethers which comprises neutralizing a perfluorinated carboxylic acid by heating with fluorine in the presence of metal fluoride to replace the carboxylic acid group.
While the above methods are useful for preparing certain fluorinated compounds, these methods are complex, expensive, and often provide fluorinated products in low yield together with considerable amounts of side products. Hence there is a need for improved procedures for the preparation of fluorinated compounds. The present invention provides such an improved procedure for preparing fluorinated compounds from the corresponding carboxylic acids in high yield and purity. More specifically, the present invention provides an improved procedure for the preparation of sevoflurane and other similar types of fluorinated anesthetics.